Heat shock proteins (HSP), or stress proteins, are families of essential proteins present in almost all prokaryotic and eukaryotic cells (Morimoto et al., Stress Proteins in Biology & Medicine, Cold Spring Harbor, N.Y. (1990)). Heat shock proteins are essential for normal cell functions and are expressed both constitutively and in increased amounts when cells are stressed in a variety of ways. Some examples of stresses that increase expression of hsp are heat, viral infection of cells, anoxia, and exposure to certain cytokines, such as tumor necrosis factor and interferon-gamma.
They are the immunodominant antigens of many bacteria and parasites, both pathogenic and non-pathogenic, and immune responses to these proteins are ubiquitous in normal individuals (Monk et al., J. Immunol., 143:2844 (1989)). Despite their ubiquity, immune responses to hsp may be important in several human and experimental diseases. (Elias et al., PNAS, 88:3088(1991); Van Eden et al., Curr Top Microbial Immuno., 147:27 (1989)). There are several examples of human and experimental autoimmune diseases associated with immune responses to hsp, especially HSP65 (Van Eden, W., Apmis, 98:383-394 (1990); Gaston, Semn. Immunol., 3:35-42 (1991)). These diseases include rheumatoid arthritis, type 1 diabetes mellitus, rheumatic diseases and systemic lupus erythmatosis. (Gaston, J. Semn. Immunol., 3:35-42 (1991)).
Several facts about hsp support their potential importance in the development of autoimmune diseases. (Jones et al., Immunol. Today, 14:115 (1993)). First, hsp are phylogenetically conserved. Thus, there is greater than 50% sequence homology between certain prokaryotic hsp and those of mammalian cells. Second, hsp are the immunodominant antigens for many infectious agents, including bacteria, mycobacteria, and parasites. The resulting strong immune response to these agents' hsp have the potential either to cross-react with the host's hsp, or with normal tissue components of the host.
It is unexpected that a universal immune response to a common family of proteins can be associated with diseases states in particular individuals. One way to reconcile this phenomenon is to postulate individual differences in the patterns of immune response to these proteins. This phenomenon is well illustrated in persons with leprosy. All infected individuals mount immune responses to the hsp of Mycobacterium leprae (M. leprae). However, some persons develop tuberculoid leprosy while others manifest the lepromatous form of the disease (de Vries, R. Am. J. Rop. Med. Hyg44(4Pt2):4-11(1991)). While the reasons for such differences are not known, several factors are important, especially the major histocompatibility complex (MHC) phenotype of the individual (Ottenhoff et al., Int. J. Lepr. Other Mycobact. Dis., 55:261 (1987)).
In addition, recent observations in several animal models indicate that autoimmune diseases are dependent upon the presence of immune responses to environmental infectious agents (Goverman et al., Cell, 72:551 (1993); Kuhn et al., Cell, 75:263 (1993)). In persons with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), attacks of presumed autoimmune demyelination frequently follow acute viral and bacterial infections (Sibley et al., Lancet, 1:1313 (1985)).
An environmental event is important for the development of MS. This is best demonstrated by the geographic distribution of the disease, which increases in frequency with distance from the equator and by migration studies which suggest that persons leaving a region of particular risk for MS prior to puberty acquire the risk of the area to which they move. Those leaving after puberty take with them the risk inherent in their original geographic location. The nature of this early environmental event is not known, but pre-pubertal exposure to an infectious agent is one possibility (Alter et al., Neurology, 36:1386 (1986)). Bacterial and viral flora change as one approaches the equator supporting the concept that the geographically specific early event involved in MS susceptibility is an infectious one (Barlow, J. S.; J. Chron. Dis.; 21: 265; 1968).
As noted above, infections are associated with exacerbations of disease. (Sibley et al., Lancet, 1:1313 (1985)). Such attacks can occur days to weeks after the acute event, usually a virus infection, and thus are not directly related to fever and acute phase reactants.
There are several possible mechanisms by which an infection can trigger a presumed autoimmune event. Cytokine levels increase during an infection and these could activate quiescent, anti-myelin specific T cells present in the CNS. An immune response to bacterial or viral-induced hsp could occur during the infection. This response may cross-react with heat shock proteins expressed in the CNS.
Thus, there is a need to identify epitopes on heat shock proteins from infectious agents that cross-react with autoantigens such as those associated with myelin since immune responses to such epitopes may trigger autoimmune diseases. There also is a need to develop methods for modulating immune responses to epitopes on heat shock proteins that are cross-reactive with autoantigens to ameliorate or prevent autoimmune diseases.